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Characterizing energy metabolism of CLL
in line with our observation.41
In our study, we also highlighted the possibility of
exploiting heterogeneity of energy metabolism to improve individualized patient care. We show that higher glycolytic flexibility can contribute to the resistance of CLL samples to treatment with drugs that affect mito- chondria, such as rotenone, venetoclax, and navitoclax. We postulate that the cytotoxic effects of these drugs may partially result from restricting the energy supply by blocking cellular respiration and thus, cells with higher glycolytic potential can counteract their effect due to high- er metabolic flexibility.
The current study has certain limitations. Firstly, while most of the proliferative activity of CLL cells appears in lymph node and bone marrow, in this study we only used circulating CLL cells due to the easier availability of patient material, which was instrumental in providing an adequate study size. In addition, although we observed many biologically meaningful associations, these are gen- erally weak, as indicated by the relatively small effect sizes or correlation coefficients. While it is possible that biological variables not measured by us contribute to the heterogeneity in energy metabolism, a likely explanation could be biological noise (since we are using patient sam- ples instead of cell lines) and technical noise of the Seahorse extracellular flux measurements, and the other
assays used. Indeed, our study is, to our knowledge, the first that uses such a dynamic assay to systematically interrogate energy metabolism on such a large scale.
Taken together, our in-depth characterization of energy metabolism and integrative analyses provide valuable insights on mechanisms underlying the metabolic regula- tion of CLL cells, and reveal the possibilities of guiding clinical diagnosis and individualized patient care based on metabolic profiles. Our large-scale energy metabolism dataset complements the current traditional omics datasets, such as RNA sequencing, DNA sequencing, and methylation profiling, and contribute to a better under- standing of CLL biology.
Acknowledgments
The authors thank the reviewers for helpful suggestions and comments, which improved the quality of this work.
Funding
The work was supported by the European Union (Horizon 2020 project SOUND) and GCH-CLL project co-founded by the European Commission/DG Research and Innovation. DM was supported by the Else Kröner-Fresenius-Stiftung. DM and MB were supported by the Erich und Gertrud Roggenbuck- Stiftung. TZ was supported by the Monique Dornonville de la Cour Stiftung and the Cancer Research Center (CRC) Zurich.
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